The development of specific and sensitive immunodiagnostic assays for Hepatitis A and Hepatitis B viruses led to the identification of several syndromes collectively known as Non-A Non-B hepatitis (NANBH or NANB hepatitis) (reviewed by Hollinger, Non-A Non-B Hepatitis. In: Fields and Knipe, eds. Virology, 2nd Ed. New York; Raven Press, pp. 2239-73, 1990). One syndrome has been clearly associated with transfusions or other percutaneous events, and has been given the name Non-A Non-B Post-Transfusion Hepatitis (NANBPTH). Another syndrome has been epidemiologically associated with fecal-oral contamination, and is known as Enteric Non-A Non-B hepatitis. A third syndrome, for which no infection event has been identified, is classified as sporadic NANBH. The application of techniques in molecular virology has served to identify a new viral agent (Hepatitis C Virus) associated with NANBPTH, Kuo et al., Science 244: 362 (1989), as well as a new viral agent (Hepatitis E Virus) associated with Enteric NANBH, Reyes et al., Science 247: 133 (1990).
Biophysical and biochemical characterization of virus-like particles from concentrated blood products or plasma implicated in the transmission of NANBPTH has been done. These studies have shown the presence of enveloped virus particles of 25-40 nm diameter whose infectivity is eliminated by treatment with organic solvents. Bradley et al., Gastroenterology 88:773 (1985). In addition, non-enveloped virus-like particles with mean diameter of 27 nm have also been observed separately, or in association with the enveloped particles just described. Bradley et al., J. Med. Virol. (1979). Cross-challenge studies can be interpreted to suggest that more than one type of viral agent may be able to cause NANBPTH. Bradley et al., J. Med. Virol. 6: 185 (1980); Hollinger et al., J. Infect. Dis. 142: 400 (1980); Yoshizawa et al., Gastroenterology 81:107 (1981).
Molecular cloning of RNA found in the plasmas of a chimpanzee and humans infected with NANBPTH have shown the presence of a viral genome of about 10 kb, Houghton et al., EPO Application No. 88310922.5 (1988); Houghton et al., EPO Application No. 90302866.0 (1990); Arima and Fukai, EPO Application No. 89309261.9 (1989); Choo et al., Science 244: 359 (1989); Okamoto et al., Japan J. Exp. Med. 60: 167 (1990); Kato et al., Proc. Natl. Acad. Sci. USA 87: 9524 (1990), with an organization similar to that of the enveloped flaviviruses or pestiviruses. Miller and Purcell, Proc. Natl. Acad. Sci. USA 87: 2057 (1990). This new virus type has been named Hepatitis C Virus (HCV), and antibodies to its encoded proteins are eventually found in approximately 60-80% of NANBPTH patients. Alter et al., New Engl. J. Med. 321: 1494 (1989); Esteban et al., New Engl. J. Med. 323: 1107 (1990); Maeno et al., Nucl. Acids Res. 18: 2685 (1990). Infectivity data consistent with Koch's postulates that clearly demonstrate HCV as a cause of NANBPTH have not been developed. However, a correlative argument can be made that many NANBPTH cases are associated with infection by HCV.
Although HCV has been widely accepted as a strong diagnostic marker for NANBPTH, it is still unclear whether other viral agents can cause this syndrome, and what role HCV plays in cases identified as sporadic NANBH. Several researchers, including one of the present inventors (T.A.), have identified cDNA sequences encoding polypeptides reactive with sera from NANBPTH patients that are not represented in the known sequences of HCV and its variants. Arima et al., Gastroenterology Jpn. 24: 540 (1989); Arima et al., Gastroenterology Jpn. 24: 545 (1989); Arima et al., Gastroenterology Jpn. 24: 685 (1989); Arima et al., Gastroenterology Jpn. 25: 218 (1990); Arima and Fukai, EPO Application No. 89309261.9 (1989). These cDNAs apparently are not encoded by the human genome, and therefore are not host-specified responses to the hepatitis disease state. Although their utility in diagnosis has been established, their source and relationship to the disease process remains obscure.